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The intoxication caused by "kiken" drugs (law-evading drugs), such as synthetic cannabinoids, cathinones, and methoxetamine, has recently increased in Japan. We retrospectively examined the characteristics of patients poisoned with the "kiken" drugs. We included patients who presented at the emergency department at the Tokyo Metropolitan Bokutoh Hospital from January 2011 to December 2014. Eighteen patients admitted between January 2011 and December 2013 were included in the early period group and 10 patients admitted between January and December 2014 were categorized into the late period group. The number of the patients transported to our emergency department between 2011 and 2014 increased annually. Patients were mainly admitted between May and October 2014; no patients were admitted after November 2014. The patients' age, history of previous mental disease, habitual use, Triage DOA results, serum creatinine values on admission, and respiratory management differed significantly between the groups. However, the median serum creatinine values of both groups on admission were within the normal level. Patients poisoned with the "kiken" drugs showed more severe symptoms, higher rate of habitual use, and higher average age. The annual increase in the number of the patients observed thus far is expected to decrease in the future. Maintenance of the law and expansion of medical institutions that treat patients addicted to the "kiken" drugs are warranted.

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Methoxetamine (MXE) is a new synthetic drug of abuse structurally related to ketamine and phencyclidine. A case of a 29-year-old male with acute toxicity related to the analytically confirmed use of MXE is reported. The man was found dead at his residence. Biological material was analyzed using liquid chromatography-tandem mass spectrometry. The concentration of MXE in urine of the deceased was 85 µg/mL. Despite the vial containing the blood sample being destroyed during transportation and the blood leaking out into the cardboard packaging, the blood level of MXE was estimated. After determination of the cardboard grammage (approx. 400 g/m(3) ) and the mean mass of the blood obtained after drying (0.1785 ± 0.0173 g per 1 mL), the estimated blood concentration of MXE was found to be 5.8 µg/mL. The high concentration of MXE in blood and urine and the circumstances of the case indicate an unintentional, fatal intoxication with this substance.

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OBJECTIVE: We conducted a multicenter retrospective survey of patients poisoned by synthetic chemicals (SCs) in Japan. METHODS: Letters were sent to 467 emergency facilities requesting participation in the study, and questionnaires were mailed to facilities that agreed to participate. Patients The study participants were patients who were transported to emergency facilities between January 2006 and December 2012 after consuming SC-containing products. RESULTS: We surveyed 518 patients from 60 (12.8%) facilities. Most patients were male (82.0%), in their 20s or 30s (80.5%), and had inhaled SCs (87.5%) contained in herbal products (86.0%). Harmful behavior was observed at the scene of poisoning for 56 patients (10.8%), including violence to others or things in 32, traffic accidents in seven, and self-injury or suicide attempts in four. Other than physical and neuropsychiatric symptoms, some patients also had physical complications, such as rhabdomyolysis (10.0%). Of the 182 patients (35.1%) admitted to hospitals, including 29 (5.6%) who needed respirators, all of the 21 (4.1%) hospitalized for at least seven days were male, and 20 had physical complications (rhabdomyolysis, 12; liver dysfunction, 5; renal dysfunction, 11; and physical injuries, 3). Most patients (95.6%) completely recovered, although 10 (1.9%) were transferred to a psychiatric department or hospital, and three (0.6%) were handed over to the police due to combative or violent behavior. SCs such as synthetic cannabinoids, synthetic cathinones, or methoxetamine were detected in 20 product samples. CONCLUSION: Consuming products containing SCs can result in physical complications, including rhabdomyolysis, injuries, and physical or neuropsychiatric symptoms, which may require active interventions, such as respirator use or prolonged hospitalization.

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Methoxetamine (MXE) is a psychoactive substance distributed mostly via the Internet and is not liable to legal regulation in Poland. MXE has a toxicity profile similar to that of ketamine but longer-lasting effects. The paper describes a case of acute poisoning that resulted from recreational use of MXE and amphetamine and ended in death. In mid-July 2012, a 31-year old man was admitted to the clinical toxicology unit in Gdansk because of poisoning with an unknown psychoactive substance. The patient was transported to the emergency department (ED) at 5:15 a.m. in a very poor general condition, in a deep coma, with acute respiratory failure, hyperthermia (> 39°C) and generalized seizures. Laboratory tests showed marked leukocytosis, signs of massive rhabdomyolysis, hepatic failure and beginning of acute renal failure. Despite intensive therapy, the patient died 4 weeks after the poisoning in the course of multi-organ dysfunction syndrome. Chemical and toxicological studies of serum and urine samples collected on the poisoning day at 1:40 p.m. confirmed that amphetamine and MXE had been taken earlier that day. Concentration of amphetamine in the serum (0.06 µg/ml) was within the non-toxic range, while MXE (0.32 µg/ml) was within the toxic range of concentrations. Amphetamine was also detected in the patient's hair, which suggested a possibility of its use within the last dozen weeks or so. The serious clinical course of intoxication and co-existence of amphetamine and MXE in the patient's blood and urine suggest the possibility of adverse interactions between them.

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INTRODUCTION: Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product Mikado(TM), which were recorded by the Angers Poison Centre. CASE REPORT: Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. DISCUSSION: In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

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The mode of action (MoA) of the herbicide mesotrione has been empirically established in experimental animals. In this review, we evaluate this MoA and the relevance of this MoA to humans against accepted scientific criteria. The key events in the MoA involve inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), the second enzyme in the tyrosine catabolic pathway, resulting in excess plasma tyrosine (tyrosinemia). When HPPD is completely inhibited, the clearance of excess tyrosine is dependent upon catabolism by the first and rate-limiting enzyme in the catabolic pathway, tyrosine aminotransferase (TAT) and elimination of the products of this catabolism via the urine. The inherent activity of TAT is low in rats and hence they catabolize tyrosine slowly and accumulate tyrosine to very high concentrations in plasma which results in a spectrum of adverse effects that are related to excess tyrosine. There is a large database showing a positive correlation between a range of biological endpoints and elevations in plasma tyrosine. Evidence is presented that clearly establishes a MoA involving tyrosine. Although plausible in humans, the extent and duration of plasma tyrosine elevation in humans is not sufficient to cause adverse effects resulting from the intended use of this herbicide.

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Methoxetamine (MXE) is a novel synthetic drug, structurally related to phencyclidine, with ketamine-like properties. Available in Poland since 2010, with no legal control, is adverti. sed as the "ideal dissociation drug". The aim of this study was to present a case of nasal methoxetamine acute poisoning in a 28-year-old man, the course of treatment, and the method of identification of this substance in serum and urine. In the course of this intoxication extreme agitation and aggression with slight response to benzodiazepines were observed. The patient was confused, hallucinated. In addition, the physical examination re. vealed tachycardia 120/min and normal blood pressure (130/80 mm Hg). The period of acute poisoning was covered by amnesia. The MXE concentrations in serum and urine were determined using liquid chromatography-mass spectrometry (LC-MS-MS) method, and were respectively 270 ng/ml and 660 ng/ml. Confirmed MXE poisoning increases our knowledge about this new substance, providing relevant clinical and analytical data.

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This paper reports an unintentional death involving the administration of methoxetamine [2-(3-methoxyphenyl)-2-(ethylamino)-cyclohexanone] and offers some reference values from living drug abusers. Methoxetamine is a new recreational drug with a similar structure to ketamine. The deceased was a 26-year-old male with a history of drug abuse; he was found lying on the floor in his apartment. Several "red-line" plastic bags were found, one of which was labeled "2-(3-methoxyphenyl)-2-(ethylamino)-cyclohexanone" and another labeled "Haze." In four cases from living subjects with unknown doses, concentrations of methoxetamine were found from 0.13 to 0.49 µg/g. In three of the cases, the blood samples also contained natural or synthetic cannabinoids. In the autopsy case, a considerably higher concentration of methoxetamine, 8.6 µg/g, was found in femoral blood. In addition, tetrahydrocannabinol and the three different synthetic cannabinoids AM-694, AM-2201, and JWH-018, were present in femoral blood. The circumstances and the high femoral blood concentration of methoxetamine point toward an unintentional, acute fatal intoxication with methoxetamine, although the presence of the three synthetic cannabinoids may have contributed to the death.

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UNLABELLED: Methoxetamine (MXE) is an analogue of ketamine. CASE REPORT: We present a 25-year-old male who, after getting an information from the Internet, started to use MXE to avoid the excitement connected with recreational codeine abuse. For about 8 - 10 months he injected about 100 mg of MXE intramuscularly. On the day of admission the patient decided to take much higher dose of 750 mg of MXE. For the first 3-4 hours of hospitalization the profound agitation, which demanded the usage of high doses of benzodiazepines, was observed every several minutes. After 6-7 hours of supportive treatment the patient returned to his baseline mental status. CONCLUSION: MXE presents the new healthcare threat because of easy accessibility via Internet, and lack of legal restrictions in many countries. The low dose of MXE can cause "peace and serenity", however, higher dose may act opposite.

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Methoxydine (4-MeO-PCP) and Methoxetamine (3-MeO-2-Oxo-PCE) are both commercially produced designer drugs with structural and biochemical similarities to phencyclidine (PCP). Although phencyclidine toxicity is well documented, its recreational use in present times is rare. With the advent of new designer drugs being available widely through internet sites, Acute Physicians should be aware of the clinical features and management of these potential toxins. We present a case of methoxydine ingestion (which to our knowledge has not been previously documented in any medical journals) and a case of methoxetamine ingestion, and discuss their history, contrasting clinical features and acute management.

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CONTEXT: There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure. CASE DETAILS: A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3-4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen. DISCUSSION: Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.

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Methoxetamine, the N-ethyl derivative of ketamine, is a novel recreational drug that is not at present subject to restrictive regulations in most countries. To our knowledge, no case of methoxetamine abuse has been published to date in the scientific literature, and the only sources of information are illegal drug users' Web discussion forums. We report the first case of analytically confirmed intravenous methoxetamine abuse in a 19-year-old man. Observed signs and symptoms such as tachycardia, hypertension, confusion, agitation, stupor, ataxia, mydriasis, and nystagmus were consistent with ketamine-induced adverse effects and resolved with symptomatic treatment. According to this case report, user Web reports, and the chemical structure, methoxetamine produces ketamine-like effects. Complete recovery can be expected with supportive care.

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OBJECTIVES: Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. METHODS: 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. RESULTS: There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone-induced hepatotoxicity. CONCLUSIONS: Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.

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A 15-year-old boy with no prior medical problems ingested cyclohexanone in a suicide attempt. The patient developed altered mental status, shock, metabolic acidosis, chemical hepatitis, and renal insufficiency. In addition, he developed rhabdomyolysis as evidenced by muscle pain, increased serum creatine phosphokinase levels and myoglobinuria. He was treated successfully with intubation, fluid resuscitation, dopamine, and activated charcoal. The patient was discharged without clinical sequelae. Renal involvement, chemical hepatitis, shock, and metabolic acidosis following oral ingestion of hydrocarbon containing solutions have been well described in the literature. To our knowledge, the development of rhabdomyolysis following an oral ingestion of a hydrocarbon was reported only once in an adult patient and never in an adolescent. We reviewed literature pertaining to the occurrence, pathophysiology, and etiology of rhabdomyolysis in hydrocarbon intoxication.

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The neurotoxic effects of acetone, methyl ethyl ketone (MEK), and cyclohexanone on Romanian workers and the impact of those effects on industry environmental standards have been controversial subjects. To scientifically substantiate the standards, a study was conducted on three groups of workers to determine the changes induced by ketone solvents on the central and peripheral nervous systems. Groups of exposed workers and matched controls were studied for each solvent: acetone, 71 exposed and 86 controls from a coin printing factory; MEK, 41 exposed and 63 controls from a cable factory; and cyclohexanone, 75 exposed and 85 controls from a furniture factory. The subjects' mean age was 36 years. The mean length of exposure was 14 years. Study participants completed a questionnaire, responded to questions about alcohol consumption, submitted to a clinical examination, submitted samples for identification of biological exposure markers, and underwent motor nerve conduction velocity and neurobehavioral tests. Results showed that workers exposed to acetone were most affected in terms of human performance and evidence of neurotoxicity, followed by workers exposed to MEK and workers exposed to cyclohexanone. On the basis of the results, it was proposed that the 6-hr permissible exposure limits for acetone, MEK, and cyclohexanone be reduced to less than 500, 200, and 150 mg/m3, respectively.

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BACKGROUND: Hepatic and neurologic injury developed in two infants after ingestion of mint tea. Examination of the mint plants, from which the teas were brewed, indicated that they contained the toxic agent pennyroyal oil. METHODS: Sera from each infant were analyzed for the toxic constituents of pennyroyal oil, including pulegone and its metabolite menthofuran. RESULTS: Fulminant liver failure with cerebral edema and necrosis developed in the first infant, who died. This infant was positive only for menthofuran (10 ng/mL). In the other infant, who was positive for both pulegone (25 ng/mL) and menthofuran (41 ng/mL), hepatic dysfunction and a severe epileptic encephalopathy developed. CONCLUSION: Pennyroyal oil is a highly toxic agent that may cause both hepatic and neurologic injury if ingested. A potential source of pennyroyal oil is certain mint teas mistakenly used as home remedies to treat minor ailments and colic in infants. Physicians should consider pennyroyal oil poisoning as a possible cause of hepatic and neurologic injury in infants, particularly if the infants may have been given home-brewed mint teas.

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